1-155904494-A-T

Position:

• chr1-155904494-A-T

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006912.6(RIT1):​c.246T>A​(p.Phe82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F82C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.0180

Genes affected

RIT1 (HGNC:10023): (Ras like without CAAX 1) This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 181522
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155904495-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 372863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 1-155904494-A-T is Pathogenic according to our data. Variant chr1-155904494-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 370035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904494-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.246T>A	p.Phe82Leu	missense_variant	5/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.297T>A	p.Phe99Leu	missense_variant	5/6		NP_001243750.1
RIT1	NM_001256820.2	c.138T>A	p.Phe46Leu	missense_variant	4/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.246T>A	p.Phe82Leu	missense_variant	5/6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460260 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	MVZ Praenatalmedizin und Genetik Nuernberg	Dec 01, 2016	wobble base substitution results in an already described pathogenic aminoacid substitution (rs730881014; Aoki et al., 2013) and was therefore rated pathogenic here. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 23791108, 25124994, 26242988, 26714497, 26757980, 27101134). ClinVar contains an entry for this variant (Variation ID: 370035). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 24469055). This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 25049390, 26757980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

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- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2021

Published in vitro studies demonstrate that variant induces elevated and prolonged phosporylation of downstream targets and strongly enhances protein-proteins interactions, consistent with a gain-of-function effect (Meyer Zum Buschenfelde et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29734338, 33190430, 26714497, 23765226) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2023

The p.F82L pathogenic mutation (also known as c.246T>A), located in coding exon 4 of the RIT1 gene, results from a T to A substitution at nucleotide position 246. The phenylalanine at codon 82 is replaced by leucine, an amino acid with highly similar properties. This variant, and other nucleotide substitutions resulting in the same amino acid change (e.g., p.F82L, c.246T>G and p.F82L, c.244T>C), have been detected in multiple unrelated individuals reported to have Noonan syndrome (NS) or features consistent with NS, including several de novo occurrences (Aoki Y et al. Am J Hum Genet, 2013 Jul;93:173-80; Bertola DR et al. Am J Med Genet A, 2014 Nov;164A:2952-7; Cavé H et al. Eur J Hum Genet, 2016 Aug;24:1124-31; Joyce S et al. Eur J Hum Genet, 2016 May;24:690-6; Kouz K et al. Genet Med, 2016 Dec;18:1226-1234; Yaoita M et al. Hum Genet, 2016 Feb;135:209-22; Liu NF et al. Lymphology, 2020;53:76-80). In vitro studies have indicated that this variant impacts protein function in a manner consistent with gain-of-function (Aoki Y et al. Am J Hum Genet, 2013 Jul;93:173-80; Meyer Zum Büschenfelde U et al. PLoS Genet, 2018 May;14:e1007370; Berger AH et al. Oncogene, 2022 May;41:2788). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.042	D
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D;D;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.026	D;T;T;.
Sift4G	Benign	0.069	T;T;T;.
Polyphen		1.0	D;.;.;.
Vest4		0.97
MutPred		0.87		Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);
MVP		0.94
MPC		2.0
ClinPred		0.98	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730881014; hg19: chr1-155874285; COSMIC: COSV64171107;